Certain 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles whose molecular structures are subsumed under the Formula (I)
wherein R1 is hydrogen, halogen, alkyl, alkoxy, predominantly fluorine-substituted alkoxy, alkanoyl, or carbethoxy; R2 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, methoxyethoxy, or ethoxyethoxy; R3 is hydrogen, C1-C3 alkyl, C2-C5 fluorinated alkyl, methoxyethyl, methoxypropyl, or ethoxyethyl; and R4 is H, C1-C3 alkyl, C2-C5 fluorinated alkyl, C1-C3 alkoxy, methoxyethoxy, or ethoxyethoxy, are known to exert the pharmacological effect in humans of inhibiting gastric acid secretion.
Among them, pantoprazole—having the systematic chemical name 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and the molecular Formula (I) wherein R1=5-OCF2H, R2═OCH3, R3═CH3 and R4═H—is a subject of U.S. Pat. No. 4,758,579.
Pantoprazole is the active ingredient of a pharmaceutical product that is marketed in the United States by Wyeth-Ayerst Inc. under the brand name Protonix®. Protonix® is approved by the U.S. Food and Drug Administration for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome. According to the package insert for Protonix®, the product contains a monosodium salt of pantoprazole (hereafter “pantoprazole sodium”) in a sesquihydrate state of hydration.
Omeprazole—having the systematic chemical name 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole and the molecular Formula (I) wherein R1=5-OCH3, R2═CH3, R3═CH3 and R4=CH3—is a subject of U.S. Pat. No. 4,508,905. It is marketed under the brand name Prilosec® by AstraZeneca for treatment of duodenal ulcer, gastric ulcer and GERD; maintenance of healing of erosive esophagitis, and long term treatment of pathological hypersecretory conditions.
Lansoprazole—having the systemic chemical name 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole and the molecular Formula (I) wherein R1═H, R2═CH3, R3═CH2CF3 and R4═H—is a subject of U.S. Pat. No. 4,628,098. Lansoprazole has utility as a drug similar to pantoprazole and omeprazole. It is marketed under the brand name Prevacid® by TAP Pharmaceutical Products for short-term treatment of duodenal ulcer, H. Pylori eradication to prevent recurrence of duodenal ulcer and maintenance of healed duodenal ulcers.
Rabeprazole—having the systematic chemical name 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and the molecular Formula (I) wherein R1═H, R2═CH3, R3═CH2CH2CH2OCH3 and R4═H—is a subject of U.S. Pat. No. 5,045,552. It is marketed in the United States under the brand name AcipHex® by Janssen Pharmaceutica Products, L.P. for healing of erosive or ulcerative GERD, maintenance of healing of GERD and treatment of symptomatic GERD.
The preparation of 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles of Formula (I) by oxidation of thioethers of Formula (II)
wherein R1, R2, R3 and R4 are as previously defined with respect to Formula (I) is generally known and is discussed in U.S. Pat. Nos. 4,758,579; 4,508,905, 4,628,098 and 5,045,552.
The '905 patent states that oxidation of thioethers of Formula (II)—wherein R1 is hydrogen, alkyl, halogen, or carbomethoxy; R2 is hydrogen, methyl, methoxy, ethoxy, methoxyethoxy, or ethoxyethoxy; R3 is methyl, ethyl, methoxyethyl, or ethoxyethyl; and R4 is methoxy, ethoxy, methoxyethoxy, or ethoxyethoxy—takes place in the presence of an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, t-butylhypochlorite, diazobicyclo-[2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine and sulfuryl chloride. MCPBA (m-chloroperbenzoic acid) was the oxidant used in the examples.
The '098 patent states that for oxidizing thioethers of Formula (II)—wherein R1 is H, methoxy or trifluoromethyl; R2 is H or methyl; R3 is H or methyl; and R4 is a C2-C5 fluorinated alkyl—the oxidizing agent is exemplified by peracid e.g. MCPBA, peracetic acid, trifluoroperacetic acid and permaleic acid, or sodium bromite or sodium hypochlorite or hydrogen peroxide. MCPBA is the oxidant that was used in Example 2 of the '098 patent.
The '552 patent states that the oxidation of thioethers of Formula (II)—wherein R1 is H, halogen, lower alkyl, lower alkoxy, halogenated lower alkyl, lower alkoxycarbonyl, or carboxyl; R2 is H or a lower alkyl group; R3 is a substituted alkoxyalkyl group; and R4 is H—can be carried out according to an ordinary process by the use of an oxidizing agent such as hydrogen peroxide, peracetic acid, MCPBA, sodium hypochlorite or sodium hypobromite. MCPBA is the oxidant used in all of the pertinent examples.
According to a general discussion in the '579 patent, compounds of Formula (I)—wherein R1 is a C1-C3 alkoxyl radical which is completely or predominantly substituted by fluorine, or a chlorodifluoromethoxy radical; R2 is H, a C1-C3 alkoxy radical, or a C1-C3 alkyl radical; R3 is a C1-C3 alkyl radical; and R4 is H, a C1-C3 alkoxy radical, or a C1-C3 alkyl radical—can be made by oxidation of sulfides under conditions known to be suitable for the oxidation of sulfides to sulfoxides. The '579 patent mentions hypohalites and peroxyacids, such as peroxyacetic acid, trifluoroperoxyacetic acid, 3,5-dinitroperoxybenzoic acid, peroxymaleic acid and MCPBA.
According to Example 6 of the '579 patent, 2-[(4,5-dimethoxy-2-pyridyl)methyl sulfinyl]-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole
is prepared by dissolving 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoro ethoxy)-1H-benzimidazole in 15 ml of dioxane and adding 2.5 ml of 1N sodium hydroxide (NaOH) solution. A mixture of 3 ml of 8% strength sodium hypochlorite (NaOCl) solution and 3.5 ml of 1N sodium hydroxide solution is added dropwise over the course of 2 hours while cooling to 0°-5° C. After addition of 5 ml of 5% strength sodium thiosulfate solution, the mixture is concentrated to dryness, the residue is taken up in water and the mixture is brought to pH 7 with phosphate buffer. The solid, which has precipitated out, is filtered off with suction, dried and recrystallized from ethyl acetate/diisopropyl ether. The yield was reported to be 55%.
From a review of the examples of the '579, '905, '098 and '552 patents, MCPBA appears to be a preferred agent for effecting oxidation of thioethers of Formula (II) to sulfoxides of Formula (1). However, MCPBA is prone to cause overoxidation of the thioether group leading to the production of sulfones of Formula (III)

An abundant literature has been generated by the overoxidation problem and numerous mild oxidants have been proposed for effecting the oxidation: WO 99/47514 (perborates), U.S. Pat. No. 5,391,752 (magnesium monoperoxyphthalate); U.S. Pat. No. 6,313,303 (perborate/acid anhydride or metal catalyst or N-halosuccinimide, 1,3-dihalo-5,5-dimethylhydantoin or dichloroisocyanurate); European Patent Publications Nos. 484,265 A (ammonium molybdate) and 302,720 (vanadium oxide); and Spanish Patents Nos. 539,793 (iodosobenzene); 540,147 (methyliodosobenzene) and 550,070 (sodium periodate).
Jozef Drabowicz, Piotr Kielbasinski and Marian MikoLaJczyk, writing before 1988, observed that in the chemical literature at that time that there had been only a single report on the use of an inorganic hypochlorite (NaOCl) for the selective oxidation of sulfides to sulfoxides. Drabowicz, J.; Kielbasinski, P.; MikoLaJczyk, M. “Synthesis of Sulphoxides”, Patai, S.; Rappoport, Z.; Stirling, C. The Syntheses of Sulphones and Sulphoxides, p. 249 (J. Wiley & Sons: New York 1988).
U.S. Pat. No. 6,423,846 discloses a process for preparing lansoprazole by Mitsunobu reaction of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine and 2-mercaptobenzimidazole followed by oxidation of the resulting thioether. The conditions of oxidation included TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as a catalyst and 2.2 equivalents of NaOCl.
It has now been discovered that when sodium hypochlorite is used as an oxidant for 2-[(pyridinyl)methyl]thio-substituted benzimidazoles under certain controlled conditions, one can obtain the sulfoxide derivative in high yield and with low levels of unreacted starting material or overoxidized side products. Those skilled in the art will immediately appreciate the economic advantages of sodium hypochlorite as an oxidizing agent. It is an inexpensive staple article of commerce. Procedures for safe handling and disposal are well established. Although sodium perborate is less costly and harmful to the environment than MCPBA, its advantages in this regard are less pronounced than those of sodium hypochlorite.